Studies of murine antibody gene organization have shown that the heavy chain variable region (VH) is comprised o several gene families. Expression of these gene families appears to be random in adult mice, by Northern analysis of B cell hybridomas and transformed cell lines. Mice that carry the xid gene defect have been shown to be unresponsive to polysaccharide antigens. In earlier studies we asked whether the lack of responsiveness to polysaccharide antigens in xid mice could be accounted for by an inability to express certain VH gene families. We showed that xid mice could express all of the 9 VH gene families examined and with normal frequencies except for the VHJ558 family in CBA/N (xid) female mice. Moreover, female CBA/N mice showed individual variation in which VH gene family was predominantly expressed. VH expression was normal in CBA/N male mice, however, suggesting that two defective X chromosomes might result in greater expression of the defect than one defective X. To further explore the relationship of the abnormal VH gene expression to the xid defect, we examined mice with the xid defect on a BALB/c background. We found that in this strain, C. CBA/N, both males and females showed individual variation in which VH gene family was predominantly expressed. Furthermore, some of the VH families that were over-expressed showed strain variation, related to the background strain and not the xid gene. For example, the S107 family was over-expressed in some CBA/N mice, but not in C.CBA/N mice. Conversely, VGam3-8 was overexpressed in C.CBA/N but not in CBA/N mice. These results indicate that the xid gene does result in abnormal VH gene family expression. Studies are in progress to determine the molecular basis for this abnormality.